Gene regulation in thyroid hormone receptor-deficient mice.

摘要

This research involves thyroid hormone signaling in thyroid hormone receptor (TR) deficient mice. TRs are nuclear hormone receptors that act as thyroid hormone dependent transcription factors. The following specific aims are discussed:; 1. Type 1 Deiodinase is mediated primarily through Thyroid Hormone Receptor beta (TRβ).; During development and in adult tissues the expression pattern of TRα1 and TRβ varies, suggesting that the two receptors mediate unique functions. This has been shown to be the case by the different phenotypes exhibited by TRα1 and TRβ deficient mice. However, because there is some co-expression of TRα1 and TRβ, the possibility of functional overlap between the two receptors exists. It is probable that for some genes the two TR isoforms are specific, but for other genes they are interchangeable.; Because the iodothyronine dediodinase type 1 gene (D1) has been shown to be positively induced by the thyroid hormone (T3) (Berry et al. 1990), it was used as a physiological marker gene to determine whether the two TRs plays a unique role, or if they share common functions in D1 regulation.; 2. Impaired auditory development in TRβ deficient mice. ; (A) Deiodinase type 2 cDNA isolation. Iodothyronine deiodinase type 2 (D2) is important in the conversion of the thyroxine, the prohormone, to triiodothyronine, the active form of thyroid hormone. At the time the project was initiated, D2 had been isolated in only several species including bull frog, human, and rat. Because our lab has thyroid hormone receptor deficient mice, a mouse clone of the D2 gene was desired. A mouse cochlear cDNA library was constructed, and a D2 cDNA containing the complete open reading frame (ORF) was obtained.; (B) Isolate candidate genes important in auditory function using the TRβ deficient mice as a model. The Thrb tml/tml mice are deaf and therefore provide an excellent model to isolate candidate genes important for auditory function. Using a differential display screen of wildtype (wt) cochlear mRNA against Thrb tml/tml cochlear mRNA a new gene named basilin (basilar membrane protein) was identified. Primary sequence analysis, tissue distribution patterns, and cellular localization of basilin within the cochlea were examined.